Discovery, α‑Glucosidase Inhibitory Activity, and Structural Optimization of the Alkaloids from Vanderbylia robiniophila SY636

α-Glucosidase inhibitory activity-guided isolation led to the discovery of ten alkaloids from the medicinal mushroom Vanderbylia robiniophila SY636, including six new compounds ((+)-1a, (−)-1b, (+)-2a, (−)-2b, 3, and (+)-4a) and four newly reported natural products ((−)-4b and 5–7). Compounds (+)-1a, (−)-1b, (+)-2a, and (−)-2b possess a unique lactam–furan ring system, whereas 3 features a rare tetrahydrobenzo[c]oxepine–furan ring system. (+)-1a, (−)-1b, (+)-4a, and (−)-4b exhibited notable α-glucosidase inhibitory activities, with IC50 values of 160–330 μM (acarbose as the positive control, IC50 = 660 μM). Guided by docking results of bioactive compounds with α-glucosidase, derivatives D1–D28 were designed and synthesized, among which D15 and D19 exhibited stronger activities (IC50 = 28 and 130 μM). Molecular docking and kinetic studies suggested that D15 and D19 interact with α-glucosidase at a single binding site, exhibiting an uncompetitive or mixed type of inhibition mechanism. D19 also exhibited notable antioxidant activity (IC50 = 35 μM), comparable to l-ascorbic acid, suggesting its dual role in combating the development of diabetes. This study provides a foundation for the development of natural medicines from V. robiniophila and offers valuable guidance for future structural optimization toward the discovery of more potent and safer antidiabetic agents.